The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology

Ines Hahn,Yu-Ting Liew,Andreas Prokop,Beatriz Costa-Gomes,André Voelzmann

doi:10.1186/s13064-019-0134-0

Abstract

Axons are the slender, cable-like, up to meter-long projections of neurons that electrically wire our brains and bodies. In spite of their challenging morphology, they usually need to be maintained for an organism's lifetime. This makes them key lesion sites in pathological processes of ageing, injury and neurodegeneration. The morphology and physiology of axons crucially depends on the parallel bundles of microtubules (MTs), running all along to serve as their structural backbones and highways for life-sustaining cargo transport and organelle dynamics. Understanding how these bundles are formed and then maintained will provide important explanations for axon biology and pathology. Currently, much is known about MTs and the proteins that bind and regulate them, but very little about how these factors functionally integrate to regulate axon biology. As an attempt to bridge between molecular mechanisms and their cellular relevance, we explain here the model of local axon homeostasis, based on our own experiments in Drosophila and published data primarily from vertebrates/mammals as well as C. elegans. The model proposes that (1) the physical forces imposed by motor protein-driven transport and dynamics in the confined axonal space, are a life-sustaining necessity, but pose a strong bias for MT bundles to become disorganised. (2) To counterbalance this risk, MT-binding and -regulating proteins of different classes work together to maintain and protect MT bundles as necessary transport highways. Loss of balance between these two fundamental processes can explain the development of axonopathies, in particular those linking to MT-regulating proteins, motors and transport defects. With this perspective in mind, we hope that more researchers incorporate MTs into their work, thus enhancing our chances of deciphering the complex regulatory networks that underpin axon biology and pathology.

Highlights

Axons are the slender, cable-like extensions of nerve cells which form the nerves and nerve tracts that wire our brain and body, sending neuronal messages in highly regulated manners
Best demonstrated so far are mechanisms dependent on ɣTuRC (ɣ-tubulin ring complexes) and their anchorage via augmin/HAUS complexes to MTs ('17' in Fig. 3): depletion of either ɣ-tubulin or different HAUS proteins causes severe axon shortening and reduction in MT density; in addition, HAUS depletion causes polarity defects reflected in frequent MT polymerisation events towards the soma [226,227,228], suggesting that regulated nucleation is doubly important for axonal MT bundle maintenance
They could link to membrane-associated proteins; for example, the mammalian spectraplakin dystonin can link to ß4-integrin and transmembrane collagen XVII ('3' in Fig. 3; [90]), and Drosophila Short stop (Shot) is able to regulate the axonal localisation of the cell adhesion molecule Fasciclin 2, potentially cross-linking Fasciclin 2 to MT bundles [376, 377]

Summary

Introduction

Cable-like extensions of nerve cells which form the nerves and nerve tracts that wire our brain and body, sending neuronal messages in highly regulated manners. Transport affects MT bundles: for example, binding of kinesin changes the physical properties of MTs (see previous section), and binding and buckling through motor proteins cause damage to the MTs they walk on, triggering maintenance responses including MT repair or potentially even replacement ('14' in Fig. 3; [120, 181,182,183,184,185]).

Results

Conclusion